Gonadotropin-reIeasing hormone (GnRH) is the ultimate regulator of reproductive function. Hypogonadotropic hypogonadism, precocious puberty, and infertility can be due to dysregulation n the GnRH neurons. The homeodomain transcription factor Otx2 has been shown to be essential or GnRH gene expression in vitro. In addition, its expression pattern and work with knockout nice suggest its role in the development of GnRH cells. This application seeks to define the role of Jtx2 in the gene expression and development of GnRH hypothalamic neurons in vivo. We will apply a CreILoxP strategy to delete the Otx2 gene in the GnRH-expressing cells and examine its effects on GnRH gene expression and developmental migration of GnRH cells. To achieve these goals, the following specific aims are proposed: 1. Develop mice with deletion of the Otx2 gene n the GnRH neurons using CreILoxP strategy; 2. Determine the effect of Otx2 on the GnRH expression in vivo; 3. Determine the effect of lack of Otx2 on the development of GnRH neurons; 4. Delete Otx2 in GnRH neurons in embryonic slice cultures. These studies will allow for a greater understanding of mechanisms underlying the gene expression and development of the GnRH ce1ls.